3. In the treatment phase of SACRED, those children with TCD velocities between 170-199 cm/sec will be eligible for protocol-directed hydroxyurea therapy. Most participants will initiate hydroxyurea treatment but those who are already on hydroxyurea and have conditional velocities will receive dose optimization. Participants will be followed until a common study termination date, defined as 3 years from the first treatment. Participants with abnormal TCD velocities ≥200 cm/sec will commence with transfusion therapy per current practice guidelines at the clinical site. Patients already on transfusion therapy identified to have conditional velocities will also be eligible for hydroxyurea and those with abnormal velocities may require re-calculation of transfusion dosing.